RBC Membrane‐Camouflaged Nanosystem‐Mediated Synergistic Drug Combination for Enhanced Anti‐Tumor Therapy

Achieving direct delivery of drugs to the tumor site is a prerequisite for successful drug development, necessitating that drug molecules be cell permeable. Numerous studies have shown that cell-penetrating peptides (CPPs) can augment the efficacy of various therapeutic agents by enhancing cellular uptake, prompting their advancement into preclinical studies. However, the non-specificity and cationic properties of CPPs impede their clinical application. Attributed to the easily accessible capacity and excellent biocompatibility of red blood cells (RBC), herein, an RBC membrane camouflaged, cell-penetrating peptides R8-(RRRRRRRR)based drug delivery system is constructed to achieve a synergistic combination of natural compounds triptolide (TP) and celastrol (Cel), thus precisely inducing tumor inhibition. The RBC membrane camouflaged nanosystem escaped from the reticuloendothelial system (RES) and is endocytosed by tumor cells mediated by R8. Released TP and Cel-induced tumor cell apoptosis, reducing tumor metastasis invasion and triggering autophagy disorder in breast cancer and liver cancer. Overall, the biomimetic nanosystem realizes enhanced drug combination therapy with high-level biosafety, which provides a facile strategy to improve the clinical application of CPPs-based drug combinations.